Medical device coated with a polymer containing a nitric oxide releasing organometallic nitrosyl compound useful for the prevention of platelet aggregation

ABSTRACT

The aggregation of platelets on the surface of a foreign body exposed to the flowing blood of a living being (such as plastic tubing, a balloon or the end of a catheter surgically inserted in a blood vessel, a stent implanted therein or synthetic grafts, which surface normal promotes such platelet aggregation to form a coating firmly affixed to that surface which would restrict the flow of blood past that surface or to form a blood clot detachable from that surface), is inhibited by a gas permeable coating on the surface of a physiologically acceptable polymer as which contains dissolved or dispersed therein a nitrosyl-containing organometallic compound, such as sodium nitroprusside, which is protected from diffusion from the coating and from direct contact with the blood and which slowly decomposes at the body temperature within the coating and in so doing releases a platelet aggregation-inhibiting amount of nitric oxide which diffuses from the coating during the period when platelet aggregation by the surface of the foreign body would be promoted in the absence of the polymer coating.

This application is a National Stage Application of PCT Application No.PCT/US97/15022, filed Aug. 27, 1997, which claims the priority and is acontinuation-in-part of U.S. application Ser. No. 08/703,646, filed Aug.27, 1996, now U.S. Pat. No. 5,797,887.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to novel drug delivery systemscontaining a nitric oxide-releasing metal compound entrapped therein andmethods for using them, more particularly for the inhibition ofrestenosis after percutaneous transluminal coronary angioplasty and forthe inhibition of acute or subacute thrombotic occlusion related to theuse or deployment of a synthetic device within the vascular tree orextracorporeally.

2. Description of the Prior Art

Sodium nitroprusside (SNP) and similar nitrosyl-containingorganometallic compounds, whether ionic salts or chelates, which canrelease nitric oxide (NO), have been known since the mid-1950's toexhibit short-term hypotensive effects. The mechanism by-which this drugelicited its pharmacological activity was not known until the discoverythat endothelial cells secreted a factor, which regulated vascular tone,termed Endothelial-Derived Relaxation Factor (EDRF) (Furchgott andZawadzki, Nature, 288: 373-376, 1980). In 1987, Palmer and coworkers(Nature, 327: 524-526, 1987) determined that the free radical nitricoxide mimicked many of the physiologic properties reported for EDRF.Besides regulating vascular tone, nitric oxide has been found to controla wide variety of physiologic functions, including (a) inhibition ofneutrophil adhesion (Kubes, et al., Proc. Natl. Acad. Sci. USA,88:4651-4655, 1991), (b) enhancement of macrophage-mediated microbialkilling (De Groote and Fang, Clin. Infect. Dis. 12 (Suppl 2): S162-S165,1995) (c) amelioration of impotence (Burnett, et al., Science, 257:401-403, 1992) and (d) regulation of various CNS functions (Dawson, etal., Ann. Neurol. 32: 297-311, 1992). Of relevance to this invention arethose studies demonstrating that nitric oxide inhibits plateletaggregation (Furlong, et al., Brit. J Pharmacol. 90: 687-692, 1987;Radomski, et al., Lancet, ii, 1057-1058, 1987) and prevents restenosis(McNamara, et al., Biochem. Biophys. Res. Commun. 193: 291-296, 1993).

Since nitric oxide regulates many physiologic functions, this freeradical is an essential ingredient for maintaining normal lifeprocesses. However, pharmacological applications of nitric oxide arelimited, since systemic use can result in severe toxicity. For instance,administration of gaseous nitric oxide systemically to treat localizedabnormalities or diseases is impractical except in a hospital intensivecare setting, because control of its dosage in the therapeutic rangecannot easily be achieved. Even if it were possible to carefully titratethe gaseous dose of nitric oxide to minimize systemic toxicity, it wouldbe very difficult to locally administer this drug to sites of interest.Therefore, the development of therapeutic agents, which would mimic thepharmacological action of nitric oxide, has received considerableattention. Several classes of nitric oxide-releasing compounds have beendeveloped, including syndnoeimine (Noack and Feelisch, J. Cardiovasc.Pharmacol. 14S: 51-55, 1989), nitroglycerin (Noack and Feelisch, J.Cardiovasc. Pharmacol. 14S: 51-55, 1989), S-nitroso derivatives(Ignarro, Lippton, Edwards, Baribos, Hyman, Kadowitz and Gretter, J.Pharmacol. Exp. Ther. 218: 729-739, 1981; Kowaluk and Fung, J Pharmacol.Exp. Ther. 255: 1254-1256, 1990; Stamler, Loscalzo, Slivka, Simon, Brownand Drazen, U.S. Pat. No. 5,380,758, 1995) and N-nitroso compounds(Maragos, Morley, Wink, Dunams, Saavedra, Hoffman, Bove, Issac, Hrabieand Keefer, J. Med Chem. 34: 3242-3247, 1991; Keefer, Dunans andSaavedra, U.S. Pat. No. 5,366,997, 1994, Keefer and Hrabie, U.S. Pat.No. 5,405,919, 1995; Keefer, Hrabie and Saavedra, U.S. Pat. No.5,525,357, 1996). These compounds require either hydrolysis or metabolicactivation, through either oxidation or reduction, to generate nitricoxide. Alternatively, several studies have reported on the developmentof photolyzed “caged-nitric oxide” compounds. For example, theorganometallic compound sodium nitroprusside has been found to releasenitric oxide upon light activation (Bates, Baker, Guerra and Harrison,Biochem. Pharmacol. 42S: S157-S165, 1991). Contrary to this, nitricoxide generation from light activation of ruthenium nitrosyl trichioridefailed to inhibit platelet aggregation, thereby questioning the utilityof this approach (Makings and Tsien, J. Biol. Chem. 269: 6282-6285,1994).

Clinically, sodium nitroprusside is used therapeutically to treathypertension acutely. Its use is limited to acute hospital-basedtreatment because this nitric oxide releasing compound has a shortlifetime of several minutes in blood (Palmer and Lasseter, New Engl. J.Med. 292: 294-297, 1975; Packer, Meller, Medine, Gorlin and Herman, NewEngl. J. Med. 301: 1193-1197, 1979). The degradation of sodiumnitroprusside is thought to arise through reductive processes takingplace in the bloodstream. Even though it has been suggested thatsulfhydryl groups attached to endothelial cells lining the vascularwalls might initiate this reaction, other reductants such as glutathioneor ascorbic acid may likewise contribute to its unusually shortphysiologic lifetime (Höbel, Kreye and Raithelhuber, Herz. 1: 130-136,1976; Ivankovitch, Miletich and Tinker, Int. Anesthesiol. Clin. 16:1-29, 1978; Kreye and Reske, Arch. Pharmacol. 320: 260-265, 1982). Basedon this pharmacological behavior, the current clinical use of this drugrequires that it is given continuously as an intravenous solution or itrapidly looses its efficacy concomitant with an increase in bloodpressure to a hypertensive level.

Apparatuses and methods have been developed for delivering nitricoxide-releasing compounds and other drugs selectively and locally to aspecific internal body site, e.g., for preventing restenosis afterpercutaneous transluminal coronary angioplasty. For instance, Cooke,Dzau and Gibbons (U.S. Pat. No. 5,428,070, 1995) described the use oforally administered L-arginine as a dietary supplement to enhance nitricoxide production by providing the substrate to nitric oxide synthase,the enzyme which metabolizes L-arginine to L-citrulline and nitricoxide. This would not be applicable to restenosis, since in thispathology, the endothelial cell levels of L-arginine are not diminished,but rather the specific isoform of nitric oxide synthase localized inendothelial cells is dysfunctional. Furthermore, even if levels ofL-arginine were low, replacement therapy through supplementation ofdietary L-arginine is an inappropriate treatment as cellular sources ofL-arginine arise primarily from the reverse metabolism of L-citrullineto L-arginine (Sessa, Hecker, Mitchell and Vane, Proc. Natl. Acad Sci.USA, 87: 8607-8611, 1990).

U.S. Pat. No. 5,282,785 employs a drug delivery apparatus comprising aflexible catheter for insertion into an internal target area of the bodyand a drug delivery means connected to the catheter. In this version,the latter delivers the drug in a radially restricted manner andcomprises (a) a drug delivery chamber at the distal end of the drugdelivery apparatus, which has a selectively permeable outer membraneportion and circumferential lips adjacent to both the proximal anddistal ends of the drug delivery system to minimize movement of a drugbeyond a segment of internal tissue and a fluid delivery passagewayextending from the chamber to the proximal end of the catheter; and (b)a non-permeable balloon affixed to and surrounding a portion of thechamber, which, when inflated, secures the chamber at the target areaand radially restricts local delivery of the drug by providing intimatecontact between balloon and a portion of the internal body tissue. Theuse of such an indwelling catheter device is limited to short termapplications (usually no longer than 10-20 minutes), because itobstructs arterial blood flow. The apparatus also includes means ofassisting the transport of the drug across the selectively permeableouter membrane with or without application of pressure.

Similarly, U.S. Pat. No. 5,286,254, also employs an apparatus,comprising a flexible catheter having a distal end and a proximal endand which is adapted for insertion into an internal area of a body; adrug delivery means having a fluid delivery passageway for delivering adrug to the distal end of the apparatus, an outer wall and a selectivelypermeable microporous outer membrane portion proximate to the distal endand an impermeable end to enhance delivery of the drug to the targetarea; and phoresis means for assisting the transport of the drug acrossthe selectively permeable membrane.

These types of apparatuses described in U.S. Pat. Nos. 5,282,785 and5,286,254 have several disadvantages. These catheter-based devicesobstruct blood flow and therefore cannot stay in the circulation systemvery long. Therefore, long-term drug delivery is not possible usingthese systems. The presence of these items in the circulatory systempromotes platelet deposition on the device.

U.S. Pat No. 5,370,614 describes the employment of a sheath coated witha matrix containing a drug and placed over the balloon of a ballooncatheter. When placed at the point of treatment, the balloon is expandedand the sheath bursts from the pressure applied, releasing the drug as abolus at the site of interest. Because restenosis occurs over a periodof weeks and treatment would likely require the slow presentation ofnitric oxide over an extended period of time, the approach of U.S. Pat.No. 5,370,614 cannot be applied to this disease condition.

U.S. Pat No. 5,470,307 describes the use of a coating to an apparatus towhich a drug is covalently bonded to a substrate on the exterior surfaceof a catheter using a linker, which photolytically releases the agentupon exposure to a light source at an appropriate wavelength. Thenecessity to photolytically break a chemical bond in order to releasenitric oxide has a clear disadvantage as there is no continued lightsource in the blood stream to cleave the linker molecule.

U.S. Pat. No. 5,278,192 describes the continual use of organic nitritesas vasodilator therapy on a chronic basis for 24 hours withoutdeveloping tolerance. The necessity of organic nitrites to bemetabolized by endothelial cells that have been made dysfunctional asthe result of a disease state would not provide a continued local fluxof nitric oxide to prevent restenosis and/or platelet aggregation at theaffected site (Munson, “Principles of Pharmacology—Basic Concepts &Clinical Applications”, pp. 482-483, 1995). Furthermore, regulatingvascular tone is not the primary purpose of our invention and the localcontrol of platelet aggregation and inhibition of intimal proliferation,leading to restenosis, altering systemic vascular tone throughadministration of either nitric oxide or a nitric oxide-releasingpro-drug is contraindicated.

U.S. Pat. No. 5,536,241 discloses a device for relaxing a smooth muscleof a hollow organ, the organ being a non-respiratory tract organcontaining a non-blood biologic fluid and a source of nitric oxide,including nitric oxide gas and an NO-releasing compound such as sodiumnitroprusside. This patent pertains to a device that does not come incontact with blood whereas our invention deals exclusively with thereactions of nitric oxide in blood, including inhibition of plateletaggregation and prevention of restenosis. In fact, the introduction ofnitric oxide as a gas into the blood is contraindicated, sincerelaxation of the underlying smooth muscle could result in severehypotension and death (see, Furchgott and Zawadzki, 1980, cited in theapplication).

U.S. Pat. No. 5,605,696 teaches that to prevent complications associatedwith insertion of a stent, such as restenosis, a polymer into which atherapeutic drug is incorporated therein, is coated onto this device.The pores of the coating have to be sufficiently large to allow the drugto diffuse from the coated stent into the blood stream of a human being.If the porosity of a coating produced by the selected polymer is notsufficient to allow the diffusion of the drug into the vasculature, aporosigen, such as lactose, is added to the polymer, thereby increasingthe porosity sufficient to achieve release of the drug onto the bloodstream. This drug delivery system allows the efficient efflux of thetherapeutic drug from the polymer into the vasculature.

In contrast to the above cited patents, our invention relates to adifferent concept, viz., coating the surface of a foreign body, such asa stent, a catheter, a synthetic vascular graft, an implantable pump, asynthetic heart valve or other intravascular device or an extracorporealdevice, such as the lumen (interior wall) of plastic tubing or theinterior surfaces of pumps used for renal dialysis or cardiopulmonarybypass, with which the flowing blood of a living being comes in contact,with a polymeric coating containing a nitrosyl-containing organometalliccompound, such as sodium nitroprusside (which is the pro-drug for nitricoxide), the drug employed in this invention, which is prevented by thecoating from leaching into the blood stream but which permits the nitricoxide produced by the decomposition thereof to diffuse therefrom (forapplications like renal dialysis or cardiopulmonary bypass)—with whichblood or body tissue would come in contact.

SUMMARY OF THE INVENTION

In an article of manufacture aspect, this invention relates to animprovement in a device adapted for exposure to blood flowing in aliving being and having a surface which is exposed to the blood andwhich is coated with a coating of a physiologically acceptable polymerwhich contains dissolved or dispersed therein a therapeutic drug,wherein the polymer coating is insoluble in the blood, inhibitsdiffusion of blood-borne reductants from entering the polymer coatingand is gas permeable and the therapeutic drug dissolved or dispersedtherein is an amount of nitrosyl-containing organometallic compoundwhich at the body temperature of the living being slowly decomposeswithin the polymer coating when the device is exposed to the blood ofthe bloodstream of the living being and in so doing releases from thecoating into the bloodstream of the living being nitric oxide at a rateeffective to inhibit the platelet aggregation which could otherwiseoccur after the device is exposed to the blood.

In a process aspect, this invention relates to a method for theproduction of a device adapted for exposure to blood flowing in a livingbeing and having a surface which is exposed to the blood which comprisesthe step of coating the surface with a coating of a physiologicallyacceptable polymer which contains dissolved or dispersed therein atherapeutic drug, wherein the polymer applied to the surface to form thecoating is insoluble in the blood, inhibits diffusion of blood-bornereductants from entering the polymer coating and is gas permeable andthe therapeutic drug dissolved or dispersed therein is an amount ofnitrosyl-containing organometallic compound which at the bodytemperature of the living being slowly decomposes within the polymercoating when the device is exposed to the blood of the bloodstream ofthe living being and in so doing releases from the coating into thebloodstream of the living being nitric oxide at a rate effective toinhibit the platelet aggregation which could otherwise occur after thedevice is exposed to the blood.

In a method of use aspect, this invention relates to a method forinhibiting the aggregation of platelets from blood flowing in a livingbeing from exposure of the blood to a foreign body by coating thesurface of the foreign surface of a device adapted for exposure to bloodflowing in a living being and having a surface which is exposed to theblood and which is coated with a coating of a physiologically acceptablepolymer which contains dissolved or dispersed therein a therapeuticdrug, wherein the polymer which -is applied to the surface to form thecoating is insoluble in the blood, inhibits diffusion of blood-bornereductants from entering the polymer coating and is gas permeable andthe therapeutic drug dissolved or dispersed therein is an amount ofnitrosyl-containing organometallic compound which at the bodytemperature of the living being slowly decomposes within the polymercoating when the device is exposed to the blood of the bloodstream ofthe living being and in so doing releases from the coating into thebloodstream of the living being nitric oxide at a rate effective toinhibit the platelet aggregation which could otherwise occur after thedevice is exposed to the blood.

In a composition of matter aspect, this invention relates to a coatingcomposition comprising (a) either an aqueous or an organic vehicle; (b)an injectable physiologically acceptable polymer dissolved or dispersedin the vehicle; and (c) a nitrosyl-containing organometallic compound,whether an ionic salt or a chelate, as defined herein which isprecipitable from vehicle, e.g., by evaporation thereof to form acontinuous coating containing the organometallic compound dissolved ordispersed therein.

DETAILED DESCRIPTION

This invention is based on the discovery that the aggregation ofplatelets in blood as a result of exposure of the blood to a foreignbody or to the injured endothelium can be inhibited by a polymer coatingon at least the surface(s) of the foreign body to which the circulatingblood is exposed which contains an amount of a nitrosyl-containingorganometallic compound, whether an ionic salt or a chelate, which isstable at room temperature but at body temperature and/or in thepresence of ambient light while the foreign body is exposed to the bloodreleases from the coating a platelet-aggregation-inhibiting amount ofnitric oxide, which amount produces a nitric oxide concentration locallyat the surface of the foreign body which cannot safely be achieved bythe systemic administration of a nitrosyl-containing organometalliccompound, whether by intravenous or intra-arterial infusion.

Thus, this invention is useful for the inhibition of restenosis, agradual re-occlusion of the blood vessel which usually occurs over aprolonged period of time, usually up to 6 weeks following trauma to theblood vessel, by providing a therapeutic concentration of NO proximateto the site of the trauma during that period of time.

In one article of manufacture aspect, this invention relates tointravascular medical devices such as synthetic (prosthetic) grafts,implantable pumps, heart valves and stents adapted for long term orpermanent insertion into the lumen of a blood vessel, e.g., inconjunction with percutaneous transluminal angioplasty. In anotheraspect, the intravascular device is adapted for temporary insertion in ablood vessel, e.g., a balloon or catheter tip.

In yet another article of manufacture aspect, this invention relates toextravascular medical devices, such as plastic tubing or a membraneinsert in the extravascular path of the blood stream of a living beingundergoing a medical procedure requiring the cycling of the blood streamor a portion thereof outside the body of the living being, e.g.,coronary artery bypass surgery or renal dialysis. In each of theseaspects of this invention, a surface of the device which is in contactwith the blood stream is coated with a polymer coating as describedherein which contains an organometallic compound as described herein.

The method of this invention provides a method of inhibiting plateletaggregation, either in the form of a layer that builds up on a medicaldevice that is permanently implanted in a blood vessel or that comes incontact with the circulating blood of a living being on a temporarybasis or in the form of a detachable clot which, if it travels to theorgans such as brain, lung, heart, kidney and liver, can be debilitatingor have life-threatening sequelae. This method also applies to stents,indwelling catheters, other intravascular devices, either temporary orpermanent, or to extracorporeal synthetic circuits for applications suchas cardiopulmonary bypass or kidney dialysis.

This invention provides a novel method for the inhibition of restenosis,i.e., a gradual reocclusion of the blood vessel over a prolonged timeperiod frequently occurring 4 to 6 weeks after surgery—by coating thesurface of the foreign body, typically a stent, that contacts the bloodwith a polymer coating of this invention which contains dissolved ordispersed therein an amount of a nitrosyl-containing organometalliccompound or a chelate which slowly decomposes within the polymer coatingwhile the stent is in position in a vascularity of a living being and inso doing releases locally an amount of nitric oxide from the coating fora time period of up to 4 to 6 weeks or longer, which is effective toinhibit restenosis.

The polymeric coating employed in this invention contains anitrosyl-containing organometallic compound, such as sodiumnitroprusside, which is a pro-drug for the nitric oxide employed as theplatelet aggregation inhibiting drug in this invention. Its porosity issufficiently low to inhibit the diffusion of the nitrosyl-containingorganometallic compound from the coating into the blood stream and alsoto inhibit blood-borne reductants from entering the polymer. The coatingis, however, gas permeable and thus does not prevent the diffusion ofnitric oxide from within the polymer coating into the blood stream.

Nitrosyl-containing organometallic compounds, whether ionic salts orchelates, employed in the composition of this invention are:

a. non-toxic, that is, substantially free from any significant toxiceffects at their effective applied concentration;

b. substantially free of symptomology, that is, they do not producesignificant symptoms detectable to the person treated at their effectiveapplied concentration;

c. relatively stable at room temperature, away from light, i.e., once anitrosyl-metal chelate is impregnated into a polymer and coated onto astent or tubing or other device, nitric oxide is not released therefromat a significant rate, e.g., during the preparation of the coating orits application to the stent, tubing or other device or thereafter,during self storage in a packaged container, is released at a rate, forexample, less than 1% per month;

d. long lasting, that is, once a stent, tubing or other intra- orextravascular device bearing on the surface thereof a coating of thepolymer impregnated with the nitrosyl-containing organometalliccompound, whether an ionic salt or a chelate, comes in contact withblood or is inserted into a blood vessel, the duration of the deliveryof nitric oxide can be adjusted by varying the concentration of thenitrosyl-containing organometallic compound in the polymer to conform tothe clinical situation to be a matter of minutes, (e.g., 5-90 minutes inthe case of a angioplasty balloon or catheter), hours (e.g., 1-4 hoursin the case of hypothennic surgery blood circulation or cardiopulmonarybypass), hours to days (e.g., 3 hours to 3 days in the case of dialysisof blood passing though plastic tubing), or days to weeks (e.g., 4 to 6weeks or longer in the case of a stent).

The Examples of a nitrosyl-containing organometallic compound employedin this invention, involve a compound of the formula [MX₅NO]⁻²Y⁺² or2Y⁺¹ where M is a transition metal such as Fe, Co, Mn, Cu, Ni, Pt; X isa negatively a charged ion such as CN, Cl, Br, I, or chelates such asEDTA, DTPA, carbamates and dithiolates that at physiologic pH havenegatively charged carboxylic and thiocarboxylic acid groups and Y is apositively charged salt.

A readily available example of the nitrosyl-containing organometallicchelates that can be employed in our invention is sodium nitroprusside,a compound in which an iron ion is complexed to five cyano groups andthe sixth ligand position is occupied by a nitrosyl group.

Exposure of the polymer coating on the surface of a device of thisinvention containing such an organometallic compound encapsulated ordissolved therein to the blood steam of a living being releases nitricoxide from the coating in a controlled manner while retaining the othernon-volatile decomposition products within the polymer coating. Theenhanced stability of sodium nitroprusside in such a polymer coating,compared to its extremely short lifetime in such a blood stream, is theresult of the inability of blood-containing reductants such as thiolsand ascorbic acid to diffuse through the polymer coating and inactivatethe sodium nitroprusside or rapidly decompose all of it, with concurrentrapid release of nitric oxide from the polymer coating, which therebyreduces or eliminates the long term benefits of prolonged release ofnitric oxide achieved by protecting the sodium nitroprusside from directcontact with, the blood stream.

Other suitable complexing agents for the iron ion areethylenediaminetetraacetic acid, EDTA; diethylenetriaminepentaaceticacid, DTPA and others of this class of chelates;1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid, DOTA andtrans-1,2-cyclohexylenediamine-N,N,N′,N′-tetraacetic acid and others ofthis class of chelates; diethylthiocarbamate and similarly relatedcarbamates; 1,2-dicyanoethylene-1,2-dithiolate and similarly relateddithiolates.

This invention relates to methods, composition and articles ofmanufacture useful in the inhibition of platelet deposition either on aforeign body introduced surgically into a blood vessel or at vascularsites which have received treatment. Examples of such medical proceduresinclude cardiopulmonary bypass during coronary artery bypass grafting(“CABG”), percutaneous transluminal angioplasty (“PTA”) of peripheralarteries, arterial bypass surgery (either peripheral or coronary) usingsynthetic (prosthetic) vascular grafts, percutaneous transluminalcoronary angioplasty (“PTCA”) with stent implantation, and renaldialysis.

The reduction of platelet deposition has important implications forreducing the incidence of restenosis occurring following balloonangioplasty. By employing a polymer coating as defined herein to coat animplantable intravascular device such as a metal stent containingdissolved or dispersed therein a nitrosyl-containing organometalliccompound in ionic salt or chelate form, nitric oxide can be locallydelivered at any desired dose profile, which can be controlled byvarying the concentration of the nitrosyl-containing organometalliccompound, the specific polymer used to form or the nature and thicknessof the coating, e.g., by employing multiple polymer coats containingvarying concentrations of the organometallic compound. Thus, systemicnitric oxide toxicity, e.g., hypotension, can be prevented fromoccurring while at the same time achieving nitric oxide level locally atthe site of the foreign body effective to inhibit platelet aggregationthereon or the formation of a detached or potentially detachablethrombus.

The nitrosyl-containing organometallic compound must be incorporatedinto a polymer coating whose porosity is sufficiently low to inhibit thediffusion of blood-borne reductants from entering the polymer andthereby inactivating the nitric oxide releasing compound of thisinvention yet is gas-permeable, i.e., has pores large enough to allowthe passive diffusion of nitric oxide from inside the polymer coatinginto the bloodstream.

The coating on the foreign body preferably is from 0.1-1.0 mm thick andcontains 1 micromole to 100 micromoles of the nitrosyl-containingorganometallic compound per mm². Higher concentrations are desirablewhen the diffusion rate of the nitric oxide from the polymer is veryslow or when it is desired that the release of the nitric oxide occursover a prolonged period of time, e.g., more than 48 hours.

A wide variety of polymers can be used to encapsulate sodiumnitroprusside and other nitrosyl-containing organometallic compounds,whether ionic salts or chelates, including both physiologically inertand biodegradable polymers and those which are only slowly soluble andthose which are insoluble in blood for at least the period of time whenany portion of the organometallic compound remains present therein.Insoluble polymers which are suitable are those which form agas-permeable membrane coating around the foreign body so that thenitric oxide can migrate therefrom as it is produced. When the foreignbody is inserted into the living being, it preferably is physiologicallyinert and, when permanently implanted, also biodegradable. Examples ofbiodegradable polymers which can be used as drug delivery systemsinclude the natural polymers: collagen, albumin, casein, fibrin andgelatin (S. Bogdansky, in: Biodegradable Polymers as Drug DeliverySystems, ed. by M. Chasin and R. Langer, Marcel Dekker,. Inc. New York,pp. 231-259, 1990). Synthetic polymer systems include polylactide andpolyglycodide (D. H. Lewis, in: Biodegradable Polymers as Drug DeliverySystems, ed. by M. Chasin and R. Langer, Marcel Dekker,. Inc. New York,pp. 1-42, 1990); polyvinyl alcohols (P. R. Byron and R. N. Dalby, J.Pharm. Sci. 76: 65-67, 1987); polyalkylene oxides and polyvinylchlorides. Other suitable polymers include polyesters, polylacticanhydrides, celluloses, vinyl copolymers, homopolymers, acrylate,polycyanoacrylate, polyurethanes, silicone polymers and other types ofpolymers, such the dendrimers.

Characteristics of an “ideal” coating for a stent is one which can beapplied to luminal or subluminal surfaces, does not cause a significantincrease in stent wall thickness; is stable over time withoutdesquamation; has a surface tension below 30 dyne/cm; has a smoothsurface texture (<1 micron irregularities) has a negative or neutralsurface charge; allows rapid endothelialization; permits timed elutionof the nitric oxide; and delivers an effective concentration of nitricoxide locally to the site (S. R. Bailey, “Coating of EndovascularStents” in: Textbook of Interventional Cardiology, ed. by E. J. Topol,Vol. 2, 2nd edition, W. B. Saunders, Philadelphia, pp. 754-765, 1994).

The desired coating can be formed by immersing the foreign body in asolution or colloidal dispersion of the selected polymer in either anaqueous or an organic vehicle containing dispersed therein thenitrosyl-containing organometallic compound, and then making the polymerinsoluble, e.g., by changing the pH or the ionic strength, by or throughevaporation of the solvent or by denaturing a proteinaceous polymer, sothat a coating of the polymer with the nitrosyl-containingorganometallic compound occluded therein deposits on the exposedsurfaces of the foreign body. For example, a stent is placed in atetrahydrofuran (THF) solution of polyvinyl chloride (PVC) in which thenitrosyl-containing organometallic compound is included therein,frequently a solid dispersed in the THF/PVC solution. The surface of thestent is thereby coated with a nitrosyl-containing organometalliccompound dissolved in a solution of THF/PVC. Upon evaporation of thesolution, the polymer encasing the nitric oxide releasing compound formsa film onto the surface of the stent.

The foreign body can be any medical device or product which has asurface that is exposed to the blood stream of a living being, whichpreferably is a human being, and is susceptible to or which promotesplatelet aggregation. Intravascular devices and angioplasty surgery ingeneral frequently promote platelet adhesion and aggregation. Placementof a stent into a living human being can also promote plateletaggregation and subsequent restenosis. Local delivery of nitric oxidecan ameliorate these life-threatening conditions. Similarly, patientsundergoing blood flow diversion outside the body, e.g., in conjunctionwith hypothermic surgery and dialysis of organs such as the kidney, haveincreased susceptibility to platelet aggregation due to a foreign bodyresponse resulting from the exposure of the blood to the plastic tubingused to transport the blood. A similar risk of foreign body responseoccurs in patients undergoing angiograms as a result of the insertion ofplastic tubing into an artery. Therefore, anticoagulants areconventionally administered (with unavoidable associated risks) tosuppress this response. When the interior of the tubing is coated withcoating according to this invention, anticoagulants can be reduced oreven eliminated entirely. Synthetic or reconstituted natural, e.g., frompowdered bone and binder, bony structures can also trigger a foreignbody response and therefore can benefit from a coating thereon accordingto this invention.

A preferred embodiment of the intravascular device aspect of thisinvention is a metal, e.g., stainless steel, or a polymericintravascular stent which typically is implanted temporarily orpermanently in a blood vessel after percutaneous transluminal coronaryangioplasty.

The intravascular or extracorporeal devices of this invention can beconstructed with pockets, grooves or other depressions in the surface ofthe device which can be filled with the polymer containing theorganometallic compound. Alternatively, the nitrosyl-containingorganometallic compound can first be deposited in the pockets, groovesor other depressions and the surface containing them and then coatedwith a polymer which does not contain the organometallic compound. Or apolymer coating containing the organometallic compound can first beformed on all of the surface(s) of the device which is exposed to theblood stream, or only a portion of that surface, and that polymercoating then covered with a protective polymer coating lacking theorganometallic compound formed from the same polymer or a differentpolymer. Alternatively, the nitrosyl-containing organometallic compoundcan be incorporated into the structure of the device itself and thedevice then covered with a protective polymer coating which allows thediffusion of nitric oxide therethrough into the blood stream.

Preferred embodiments of the devices of this invention comprise one ormore of the following:

a. The device is an intravascular device adapted for insertion into thebloodstream of the living being.

b. The intravascular device is in the form of a balloon, a catheter or astent adapted to be inserted surgically into a blood vessel of a livingbeing in conjunction with transluminal coronary angioplasty.

c. The intravascular device is a stent and the nitrosyl-containingorganometallic compound is sodium nitroprusside.

d. The intravascular device has the nitrosyl-containing organometalliccompound positioned within pockets, grooves or other depressions in thesurface of the device and is covered with a coating of thephysiologically acceptable polymer.

e. The coating containing the nitrosyl-containing organometalliccompound is coated with a second coating of the same or differentpolymer that does not contain the organometallic compound.

f. The device is an extravascular device adapted to transport the bloodof a patient undergoing coronary artery bypass surgery or renaldialysis.

g. The device is an extravascular device which comprises plastic tubingthat is adapted to transport the blood and whose inner surface is coatedwith the polymer coating.

h. The extravascular device has the polymer coating on the surface of amembrane insert or on the inner surface of a section of the plastictubing coated with the polymer coating, which is otherwise uncoated,which contacts the blood stream.

i. The extravascular device has sodium nitroprusside as thenitrosyl-containing organometallic compound.

The preferred methods for the production of a device of this inventionand the preferred methods of using such a device also involve one ormore of the above described preferred embodiments of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 shows the exterior, interior and cross sectional views of aplatelet-inhibition element of this invention comprising a containeradapted to be inserted in the blood flow loop of a patient undergoingrenal dialysis or surgery involving extravascular transport of the bloodstream of the patient and an accordion folded biologically inertsynthetic polymer mesh insert for the container through which the bloodof the patient must flow; and

FIG. 2 shows the side view (FIG. 2A) and cross sectional top view of astent (FIG. 2B) of this invention which contains grooves in the innerwalls thereof for deposition of the organometallic compound. FIG. 2C isan end view of the cross sectional section of the stent with theorganometallic compound deposited in the grooves and covered with thepolymer coating of this invention.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. The entire disclosures of all applications, patents andpublications, cited above and below are incorporated by reference. Thefollowing preferred specific embodiments are, therefore, to be construedas merely illustrative and not limiting to the disclosure in anywaywhatsoever.

EXAMPLE 1

Preparation of Nitric Oxide Delivery Systems. A 5% (w/w) of polyvinylchloride (PVC, inherent viscosity 1.02, M.W. 40,000-85,000) solution wasprepared by dissolving PVC (5 gm) in tetrahydrofuran (100 mL) at roomtemperature for 1 hour. After this PVC solution was prepared, sodiumnitroprusside (1 gm SNP) was mixed with the PVC solution to give aSNP/PVC/THF suspension. Polyvinyl chloride tubing was coated with eitherPVC containing SNP or with PVC alone by allowing the solution of PVCcontaining the SNP or the corresponding solution containing only the PVCto flow through the tubing. After air drying the tubing, the coatingprocess is repeated a number of times to obtain a coating containing theamount of SNP required to produce the desired flux of nitric oxide. Oncethe desired release rate of nitric oxide is achieved, a THF/PVC solutioncan be placed over the dried PVC containing SNP. In this manner, SNP isprotected by an additional coating of PVC alone from blood elements,which rapidly inactivate SNP. Other surfaces, such as plastic Falcontubes or glass coverslips, were coated in a similar manner.

EXAMPLE 2

Kinetics of Nitric Oxide Release from Plastic Surfaces. A plastic tubewas coated with a solution of polyvinyl chloride (PVC, inherentviscosity 1.02, M.W. 40,000-85,000, solution was prepared by dissolving5 gm of PVC in 100 mL tetrahydrofuran at room temperature for 1 hour)containing particulate sodium nitroprusside (<38 microns; 0.5% w/v). Thesolvent was removed by air drying to leave a polymer coating 0.1 to 1 mmthick. Nitrite accumulation using the Griess reagent in a sodiumphosphate buffer was used as a measure of nitric oxide. Samples of thebuffer was removed and analyzed daily, thereby ensuring that thedetermination of nitrite (a measure of nitric oxide) gave an accurateaccount of the daily release of nitric oxide. Samples (0.6 mL) weretaken and added to freshly prepared Griess's reagent (0.4 mL of 0.1%N-(1-naphthyl)-ethylenediamine in water and 1% sulfanilamide in 5%phosphoric acid mixed 1:1). This reaction incubates for 15 minutes atroom temperature and absorbance is recorded at 550 nm. Concentrations ofnitrite were estimated by comparing absorbances at 550 nm againststandard solutions of sodium nitrite prepared in the same buffer (Green,Wagner, Giogowski, Skipper, Wishnok and Tannebaum, Anal. Biochem. 126:131-138, 1982). The first few days of nitric oxide release from thepolymer into the phosphate buffer at 37° C. was high, achieving amaximal concentration of approximately 35 micromolar of nitric oxide byday 3. At this point, the concentration of nitric oxide decreasedslowly, achieving, by day 35, an equilibrium flux of 8 micromolar ofnitric oxide. This rate of nitric oxide release remained constant for 52days, when the experiment was terminated. These results demonstrate thatsodium nitroprusside incorporated into a PVC coating can release nitricoxide into a phosphate buffer at 37° C. in the absence ofblood-containing reductants.

EXAMPLE 3

An in vivo experiment was employed to evaluate the ability of a polymercoating, produced by casting a solution of polyvinyl chloride (PVC,inherent viscosity 1.02, M.W. 40,000-85,000, solution was prepared bydissolving 5 gm of PVC in 100 mL tetrahydrofuran at room temperature for1 hour) containing particulate (<38 microns; 0.5% w/v) sodiumnitroprusside dispersed therein onto the lumen of PVC tubing and airdrying to remove the solvent, to inhibit platelet aggregation. Anartificial A-V fistula was created between the femoral artery and veinof a pig with PVC- and PVC/SNP-coated tubing connected in parallel. Theflow rate in the A-V fistula tubing was adjusted to 80 mL/min. Bloodsamples were taken for ADP-induced platelet aggregation and measurementof serum nitrite concentrations at locations close to the femoral arteryand at the distal end of the PVC-coated and PVC/SNP-coated tubing.Samples were collected every hour after establishing the artificial A-Vfistula and 20 minutes after the disconnection of the fistula. After theblood pressure was stabilized at about 75 mm Hg, the flow through thetubing was begun. One hour after establishing the A-V fistula, bloodsampled from the PVC/SNP-coated tubing showed 69% inhibition of plateletaggregation as compared to 24% inhibition for blood sampled from theuncoated control tubing. Of interest is the finding that even after 4hours of flow through the PVC/SNP-coated tubing during which plateletaggregation remained markedly inhibited (platelet inhibition of thePVC/SNP-coated tubing at over 200% of control), blood pressure wasunchanged, remaining at about 75 mm Hg. It is clear from these data thata slow release of nitric oxide through the PVC polymer inhibits plateletaggregation as compared to the control, PVC alone.

Biologic Assay for Nitric Oxide—Platelet Aggregation. Aggregation ofhuman platelets was measured optically with a four-channel plateletaggregometer (Model 560-Ca, Chromolog, Havertown, Pa.). Venous blood wascollected in a citrated tube, centrifuged at 250×g to isolate plateletrich plasma (PRP, platelet count with approximately 300,000/mL).Platelet aggregation was induced by ADP (10 micromolar, finalconcentration).

EXAMPLE 4

The fact that selective diffusion is achievable by our invention wasverified by the following experiments, which were designed to test therelative diffusiveness of sodium nitroprusside (a readily availableexample of the general class of nitrosyl-containing organometalliccompounds employed in our invention) and nitric oxide through apolyvinyl chloride coating.

A solution of sodium nitroprusside (10 mM in sodium phosphate buffer, pH7.4) was placed within a PVC tube (the inner tube) and sealed. A secondlarger PVC tube (the outer tube) filled with only sodium phosphatebuffer at pH 7.4 was fitted around the inner tube containing thesolution of SNP and it also was sealed. This device was placed on alaboratory bench and maintained at ambient conditions for 3 days. Atthis point, the contents of each of the sealed tubes were analyzed.

We analyzed for SNP in each tube. The analysis showed that the innertube contained residual SNP and the non-volatile components of theportion of the SNP which had decomposed, as shown by the UV-visiblespectrum analysis for SNP in the phosphate buffer. In contrast, thecontents of the outer tube did not exhibit any UV-visible spectrumabsorption. These findings demonstrate that the sodium nitroprusside didnot diffuse through the wall of the inner tube into the outer tube. Wealso analyzed for nitric oxide to determine whether the nitric oxideproduced by the decomposition of the sodium nitroprusside in thesolution in the inner tube had diffused into the outer tube. We did soby measuring the amount of nitrite present, which provides an estimateof nitric oxide content, using the method of Green, et al., (Anal.Biochem. 126: 131-138, 1982). This analysis demonstrated that 80micromolar nitrite had accumulated in the outer tube, thus confirmingthat nitric oxide had diffused from the inner tubing into the outertubing, whereas the SNP had not.

Taken together, these experiments proved that the sodium nitroprussidein the inner tube had decomposed and produced nitric oxide and theporosity of the coating was sufficiently small to prevent sodiumnitroprusside from migrating therefrom and collecting in the outer tubebut was gas permeable and therefore did not prevent the nitric oxidegenerated in the inner tube from diffusing through the wall thereof intothe buffer solution in the outer tube.

EXAMPLE 5

Construction of a platelet-inhibition element. A platelet-inhibitionelement (FIG. 1) may be constructed by placing a large surface areafilter into a cylindrical device which then can be inserted into anextracorporeal blood pathway during procedures such as cardiopulmonarybypass surgery and renal dialysis. The membrane and/or the internalsurfaces of the cylinder can be coated with a polymer into which thenitrosyl-containing organometallic compound is incorporated therein. Apreparation of this nitric oxide delivery system is as follows: A 5%(w/w) of polyvinyl chloride (PVC, inherent viscosity 1.02, M.W.40,000-85,000) solution is prepared by dissolving PVC (5 gm) intetrahydrofuran (100 mL) at room temperature for 1 hour. After this PVCsolution is prepared, sodium nitroprusside (1 gm SNP) is mixed with thePVC/THF solution to give a SNP/PVC/THF suspension. The membrane and/orthe internal surfaces of the platelet-inhibition element are coated withPVC containing SNP by allowing the corresponding solution to flowthrough the device. After air drying the device, the coating process canbe repeated a number of times to obtain the desired flux of nitricoxide.

EXAMPLE 6

Construction of a drug-delivery stent. The stent (FIG. 2) is constructedof metal in which grooves are created along its length into which anitrosyl-containing organometallic compound can be placed. This surfacein which the nitrosyl-containing organometallic compound is placed isthen covered with a physiologically acceptable polymer. A preparation ofthis nitric oxide delivery system is as follows: First sodiumnitroprusside (1 gm SNP) is ground, and the resulting powder placed inthe grooves of the stent. Then a 5% (w/w) of polyvinyl chloride (PVC,inherent viscosity 1.02, M.W. 40,000-85,000) solution is prepared bydissolving PVC (5 gm) in tetrahydrofuran (100 mL) at room temperaturefor 1 hour. This solution is then coated over the grooves on the stentcontaining the sodium nitroprusside. After air drying the drug deliverystent, the coating process can be repeated a number of times to obtainthe desired flux of nitric oxide. In this manner, SNP is protected fromblood elements, which rapidly inactivate SNP, by the coating of PVCalone.

What is claimed is:
 1. A medical device comprising a surface coated witha physiologically acceptable polymer which contains dissolved ordispersed therein a nitrosyl-containing organometallic compound, whereinthe polymer coating is insoluble when in contact with blood for at leasta period of time when any portion of the organometallic compound remainspresent therein, inhibits diffusion of reductants into the coating,inhibits the release of the nitrosyl-containing organometallic compoundand releases nitric oxide when the device is inset in contact with inblood.
 2. The device according to claim 1, wherein the coating is fromabout 0.1 mm to about 1.0 mm thick.
 3. The device according to claim 1,wherein the coating contains from about 1 mmole/mm² to about 100mmole/mm² of the nitrosyl containing organometallic compound.
 4. Thedevice according to claim 1, wherein the device is an intravasculardevice adapted for insertion into the blood stream.
 5. The deviceaccording to claim 4, in the form of a balloon, a catheter or a stent.6. The device according to claim 1, wherein the device is adapted to beinserted surgically into a blood vessel in conjunction with transluminalcoronary angioplasty, a prosthetic vascular graft, implantable pump orheart valve.
 7. The device according to claim 1, wherein thenitrosyl-containing organometallic compound is sodium nitroprusside. 8.The device according to claim 1, wherein the coating containing thenitrosyl-containing organometallic compound is coated with a secondcoating of the same or a different polymer that does not contain thenitric oxide releasing organometallic compound.
 9. The device accordingto claim 1, wherein the device comprises plastic tubing and surfaces,polytetrafluorethylene tubing and surfaces or a metal surface.
 10. Thedevice according to claim 1, wherein the coating is applied to an innersurface of the device.
 11. The device according to claims 10, whereinthe device is adapted to transport the blood of a patient undergoingcoronary bypass or renal dialysis.
 12. The device according to claim 10,wherein the coating is applied to only a section of the inner surface ofthe device.
 13. The device according to claim 1, wherein the coating ison a separate insert in an extravascular tube.
 14. A medical devicecomprising a surface coated with a physiologically acceptable polymercoating which encapsulates a nitrosyl-containing organometallic compoundwherein the polymer coating is insoluble when in contact with blood forat least a period of time when any portion of the organometalliccompound remains present therein, inhibits the release of thenitrosyl-containing organometallic compound and is gas permeable. 15.The device according to claim 14, wherein the polymer inhibits diffusionof reductants into the coating.
 16. The device according to claim 14,wherein the coating allows nitric oxide produced from the nitrosylcontaining organometallic compound to migrate from the coating.
 17. Thedevice according to claim 14, wherein the device is adapted to bepermanently implanted.
 18. The device according to claim 14, wherein thepolymer coating comprises a biodegradable polymer.
 19. The deviceaccording to claim 14, wherein the polymer coating comprises a syntheticpolymer.
 20. The device according to claim 19, wherein the syntheticpolymer is selected from the group consisting of polyalkylene oxides,polyvinyl chloride, polyester, polylactic anhydride, cellulose, vinylpolymers, acrylates, polycyanoacrylates, polyurethanes and siliconepolymers.
 21. The device according to claim 14, wherein the polymer hasa surface tension below about 30 dyne/cm.
 22. The device according toclaim 14, wherein the coating has a smooth texture.
 23. The deviceaccording to claim 14, wherein irregularities in the coating surface areless than 1 micron in size.
 24. The device according to claim 14,wherein the coating surface is neutral or has a negative charge.
 25. Thedevice according to claim 14, wherein the coating allows rapidendothelialization.
 26. The device according to claim 14, wherein thecoating permits timed elution of nitric oxide.
 27. The device accordingto claim 14, wherein the coating elutes a concentration of nitric oxideeffective to prevent platelet aggregation.
 28. The device according toclaim 14, wherein the coating allows elution a concentration of nitricoxide effective to prevent restenosis.